PROJECT SUMMARY: Neurodegenerative disorders are characterized by abundant protein aggregates in brain and spinal cord (CNS) that are the defining neuropathology (NP) of these disorders as exemplified by senile plaques (SPs) and neurofibrillary tangles (NFTs), the diagnostic signatures of Alzheimer's disease (AD). However, AD is associated with Lewy bodies (LBs) and TDP-43 pathologies in >50% of patients while mild cognitive impairment (MCI) often shows abundant SPs and NFTs at autopsy consistent with AD. Further, the NP in ~25% or more of frontotemporal lobar degeneration (FTLD) patients is AD, while the remaining FTLD cases are non-AD tauopathies (FTLD-Tau), TDP-43 proteinopathy (FTLD-TDP) or, rarely, FUS proteinopathy (FTLD-FUS). Thus, a definitive diagnosis of AD and related dementias is established definitively only by postmortem NP examination, and an accurate NP diagnosis is essential for informative clinicopathologic correlations to elucidate molecular mechanisms of MCI, AD, FTLD and other dementias such as Parkinson's disease with dementia and dementia with LBs. Since multiple genetic factors contribute to the risk for AD and biomarkers signal disease onset/progression, DNA and biofluid banking is critical for genetic and biomarker studies. Hence, the University of Pennsylvania (Penn) AD Core Center (ADCC) characterizes and banks CNS tissues, DNA and biofluids from well-characterized patients followed in Clinical Core B with AD and related disorders as well as normal control subjects. This is essential for research conducted in ADCC Pilots and other grants that utilize Penn ADCC resources. Accordingly, Core D is re-named the Neuropathology, Genetics and Biomarker Core to reflect the full scope of its current activities. Core D also distributes tissue, DNA and biofluids to investigators at and beyond Penn for research. Finally, Core D works with the Data Management and Statistics Core C to enter all information into a database, maintain data confidentiality, and provide these data to NACC. In summary, Core D performs critical functions to support the mission of the Penn ADCC.